Restriction of iron availability by ferroportin inhibition is a novel approach to treating non-transfusion-dependent thalassemia (β-thalassemia intermedia). This first-in-human, Phase I study (https://www.clinicaltrialsregister.eu; EudraCT no. 2017-003395-31) assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of singleand multiple-ascending doses (SAD and MAD) of the oral ferroportin inhibitor, VIT-2763, in healthy volunteers. Participants received VIT-2763 5/15/60/120/240 mg or placebo in the SAD phase and VIT-2763 60/120 mg once daily, VIT-2763 60/120 mg twice daily, or placebo for 7 days in the MAD phase. Seventy-two participants completed treatment. VIT-2763 was well tolerated and demonstrated a similar safety profile to the placebo. There were no serious or severe adverse events, or discontinuations due to adverse events. VIT-2763 absorption was relatively fast, with detectable levels 15 to 30 minutes post-dose. Following multiple dosing there was no apparent change in absorption and accumulation was minimal. Mean elimination halflife was 1.9 to 5.3 hours following single dosing, and 2.1 to 3.8 hours on Day 1 and 2.6 to 5.3 hours on Day 7, following repeated dosing. There was a temporary decrease in mean serum iron levels with VIT-2763 single doses ≥60 mg and all multiple doses; mean calculated transferrin saturation (only assessed following multiple dosing) also temporarily decreased. A shift in mean serum hepcidin peaks followed administration of all iron-lowering doses of VIT-2763. This effect was less pronounced after 7 days of multiple dosing (aside from with 120 mg once daily). These results support the initiation of clinical studies in patients with non-transfusion-dependent thalassemia and documented iron overload due to ineffective erythropoiesis.

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Ferric carboxymaltose (FCM) has been shown to achieve rapid replenishment of iron stores and correction of anaemia in various populations with iron deficiency. A decrease in serum phosphate (PO43−) levels, which in most cases is asymptomatic, has been reported with IV iron preparations. Hypophosphataemia (HP) is a known adverse drug reaction with FCM. This post hoc pooled analysis investigates the frequency, duration, risk factors, and clinical signs of HP as reported in interventional clinical trials with FCM. Pooled data from subjects enrolled across 45 clinical trials in different therapy areas were included. A three-step adjudication process was utilised to identify adverse events of HP. Stratified analyses by therapy group and stepwise logistic regression analysis were used to identify predictors of HP. This pooled analysis confirms that FCM is associated with increased rates of serum PO43− lowering, but mean serum PO43− values were seen to recover at Week 4 and further recover at Week 8. Among all subjects receiving FCM therapy (n = 6879), 41.4% (n = 2847) reached a PO43− nadir value <2.5 mg/dL at any point on study and 0.7% (n = 49) reached a nadir <1 mg/dL. Although gastroenterology and women’s health subjects were identified to be at higher risk, occurrence of severe HP (<1 mg/dL [0.3 mmol/L]) following FCM administration was not observed to be common among subjects in these studies. Furthermore, there was no correlation between laboratory serum PO43− values and the occurrence of reported adverse events related to low PO43− levels.

In patients with current or a history of hyperkalaemia, treatment with renin-angiotensin-aldosterone system inhibitors (RAASi) is often compromised. Patiromer, a novel potassium (K + ) binder, may improve serum K + levels and adherence to RAASi.

Background Reduced kidney function is common among patients with heart failure. In patients with heart failure and/or kidney disease, iron deficiency is an independent predictor of adverse outcomes. In the AFFIRM-AHF trial, acute heart failure patients with iron deficiency treated with intravenous ferric carboxymaltose demonstrated reduced risk of heart failure hospitalization, with improved quality of life. We aimed to further characterize the impact of ferric carboxymaltose among patients with coexisting kidney impairment. Methods The double-blind, placebo-controlled AFFIRM-AHF trial randomized 1132 stabilized adults with acute heart failure (left ventricular ejection fraction <50%) and iron deficiency. Patients on dialysis were excluded. The primary endpoint was a composite of total heart failure hospitalizations and cardiovascular death during the 52-week follow-up period. Additional endpoints included cardiovascular hospitalizations, total heart failure hospitalizations, and days lost to heart failure hospitalizations or cardiovascular death. For this subgroup analysis, patients were stratified according to baseline estimated glomerular filtration rate (eGFR). Results Overall, 60% of patients had an eGFR <60 ml/min/1.73 m2 (the lower eGFR subgroup). These patients were significantly older, more likely to be female and to have ischemic heart failure, and had higher baseline serum phosphate levels and higher rates of anemia. For all endpoints, event rates were higher in the lower eGFR group. In the lower eGFR group, the annualized event rates for the primary composite outcome were 68.96 and 86.30 per 100 patient-years in the ferric carboxymaltose and placebo arms, respectively (rate ratio, 0.76; 95% confidence interval, 0.54–1.06). The treatment effect was similar in the higher eGFR subgroup (rate ratio, 0.65; 95% confidence interval, 0.42–1.02; P interaction=0.60). A similar pattern was observed for all endpoints (P interaction>0.05). Conclusions In a cohort of patients with acute heart failure, left ventricular ejection fraction <50%, and iron deficiency, the safety and efficacy of ferric carboxymaltose were consistent across a range of eGFR values.

Background Iron plays a key role in human immune responses; however, the influence of iron deficiency on the coronavirus disease 2019 (COVID-19) vaccine effectiveness is unclear. Aim To assess the effectiveness of the BNT162b2 messenger RNA COVID-19 vaccine in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19–related hospitalization and death in individuals with or without iron deficiency. Methods This large retrospective, longitudinal cohort study analyzed real-world data from the Maccabi Healthcare Services database (covering 25% of Israeli residents). Eligible adults (aged ≥16 years) received a first BNT162b2 vaccine dose between December 19, 2020, and February 28, 2021, followed by a second dose as per approved vaccine label. Individuals were excluded if they had SARS-CoV-2 infection before vaccination, had hemoglobinopathy, received a cancer diagnosis since January 2020, had been treated with immunosuppressants, or were pregnant at the time of vaccination. Vaccine effectiveness was assessed in terms of incidence rates of SARS-CoV-2 infection confirmed by real-time polymerase chain reaction assay, relative risks of COVID-19–related hospitalization, and mortality in individuals with iron deficiency (ferritin <30 ng/mL or transferrin saturation <20%). The two-dose protection period was Days 7 to 28 after the second vaccination. Results Data from 184,171 individuals with (mean [standard deviation; SD] age 46.2 [19.6] years; 81.2% female) versus 1,072,019 without (mean [SD] age 46.9 [18.0] years; 46.2% female) known iron deficiency were analyzed. Vaccine effectiveness in the two-dose protection period was 91.9% (95% confidence interval [CI] 83.7–96.0%) and 92.1% (95% CI 84.2–96.1%) for those with versus without iron deficiency (P = 0.96). Of patients with versus without iron deficiency, hospitalizations occurred in 28 and 19 per 100,000 during the reference period (Days 1–7 after the first dose), and in 19 and 7 per 100,000 during the two-dose protection period, respectively. Mortality rates were comparable between study groups: 2.2 per 100,000 (4/181,012) in the population with iron deficiency and 1.8 per 100,000 (19/1,055,298) in those without known iron deficiency. Conclusions Results suggest that the BNT162b2 COVID-19 vaccine is >90% effective in preventing SARS-CoV-2 infection in the 3 weeks after the second vaccination, irrespective of iron-deficiency status. These findings support the use of the vaccine in populations with iron deficiency.

Background ECCO guidelines acknowledge the limitations of oral iron for iron deficiency anaemia in IBD and recommend first-line IV iron in patients with active disease. Ferric carboxymaltose (FCM) is approved for iron deficiency when oral iron is ineffective/inappropriate. FCM has shown benefit in RCTs, and as with other IV irons, is known to cause a transient decrease in serum phosphate (PO4), which in most cases is asymptomatic. The aim of this pooled analysis was to characterise the frequency, duration, risk factors, and clinical signs of hypophosphataemia (HP) across 45 interventional trials with FCM. Methods 15,080 subjects were included (FCM n = 8,245; controls n = 6,835). 12,683 had post-baseline serum PO4 measurements (FCM n = 6,879), which were pooled by time-point, clinical characteristics, dose, and iron parameters. Serum PO4 thresholds were: 2.5–&lt;4.5 mg/dl (normal), 2.0–&lt;2.5 mg/dl (mild decrease), 1–&lt;2.0 mg/dl (moderate), and &lt;1 mg/dl (severe). Logistic regression analysis was used to identify predictors of HP. MedDRA terms were interrogated for reported and potential clinical signs of HP. Results 2,760 FCM subjects (40.1%) with normal PO4 at baseline developed HP (PO4 &lt;2.5 mg/dl) on study. PO4 levels normalised in 1,705 subjects (61.8%); mean time to normalisation (±SD) was 40.7 days (±35.31). PO4 normalisation during follow-up did not occur in 177 subjects (0.06%). Independent risk factors for moderate/severe HP within 12 weeks of treatment included treatment setting (gastroenterology or neurology vs. women’s health), lower baseline ferritin level, maximum single-dose, advanced age, lower weight at baseline (all p &lt; 0.0001), multiple doses vs. single dose (p = 0.0003), and higher cumulative dose (p = 0.0005). ‘Hypophosphataemia’ as a MedDRA term was approximately 10-fold more frequent with FCM than controls (2.2% vs. 0.2% with other IV irons). Potential clinical signs of HP were not more frequent with FCM vs. controls (Table) and were not associated with nadir levels of serum PO4. 4 of 49 FCM subjects (8.2%) who had nadir PO4 below 1 mg/dl had a potential clinical sign of HP, vs. 126/1,569 (8.0%) with 1–&lt;2.0 mg/dl, 113/1,229 (9.2%) with 2.0–&lt;2.5 mg/dl and 411/4,032 (10.2%) with ≥2.5 mg/dl. Among subjects with PO4 &lt;2.5 mg/dl, serious cardiac disorders classified as potentially related to HP occurred in 14 FCM subjects (0.5%), 1 (0.7%) other IV iron, and 2 (4.4%) oral iron. Conclusion HP is recognised as a common adverse drug reaction with FCM as with several other IV iron preparations. This analysis shows that the transient decreases in PO4 levels were more frequent in patients receiving multiple and/or large doses of FCM but were not associated with an increased rate of potential signs/symptoms of HP.

Background:Ferroportin (FPN), the only known iron transporter in mammals, is mainly expressed in tissues of iron absorption (duodenum), recycling and storage (liver and mononuclear phagocyte system). Through its action on FPN, hepcidin controls plasma iron levels. VIT‐2763 is the first oral FPN inhibitor that has been shown to lower plasma iron levels in preclinical pharmacology studies. In addition, VIT‐2763 ameliorated ineffective erythropoiesis in a thalassemia disease model.Aims:A Phase I, first‐in‐human, double–blind, randomized, placebo‐controlled study was performed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of single‐ and multiple‐ascending doses (SAD and MAD) of VIT‐2763 in healthy male or female subjects. EudraCT no. 2017–003395‐31.Methods:In Part A (SAD), subjects received a single oral dose of VIT‐2763 in five cohorts: 5/15/60/120/240 mg. Part B (MAD) involved four VIT‐2763 dose cohorts: oral VIT‐2763 60/120 mg once daily (QD) or 60/120 mg twice daily (BID) for 7 days. In both parts, subjects were randomized 3:1 into each cohort to receive VIT‐2763 or placebo. Safety and tolerability (primary endpoint) were assessed throughout. Serial blood samples were collected for analysis of PK and PD (including but not limited to serum iron and hepcidin levels). PK parameters were determined by non‐compartmental analysis.Results:In Parts A and B, 38 (29 active, 9 placebo) and 34 subjects (26 active, 8 placebo) were enrolled respectively.Treatment with single and multiple oral doses was well tolerated. In Part A, 32 treatment‐emergent adverse events (TEAEs), all of which were mild, occurred in 53% of subjects; in Part B, 96 TEAEs (all mild/moderate) occurred in 85% of subjects. All TEAEs were transient and self‐limiting. There were no findings of clinical relevance with respect to vital signs, 12‐lead ECG, telemetry or physical examination. There were no serious or severe TEAEs nor discontinuations due to TEAEs following single or multiple dosing.The initial oral absorption of VIT‐2763 was relatively fast; most subjects had detectable levels 15–30 min post dose and median Tmax was 0.5–3 hours. A second peak in the concentration–time profile occurred 3–4 hours post dose. The exposure over the dose range of 5–240 mg was slightly more than dose proportional for Cmax, AUC0last and AUC0‐inf. Following multiple oral dosing up to 120 mg BID for 7 days there was no apparent change in absorption and accumulation was minimal. The geometric mean elimination t 1/2 was 1.8–5.3 hours following single dosing, and 2.1‐3.8 hours on Day 1 and 2.6–5.3 hours on Day 7, following repeated dosing.Single and multiple doses of VIT‐2763 ≥60 mg lowered serum iron, which remained below baseline values for up to 24 hours post‐dose, following BID dosing in the MAD phase (see Figure). There was also a temporary increase in mean serum hepcidin levels. This iron‐lowering pharmacodynamic effect is consistent with observations in preclinical models. No dose‐related effects were observed with respect to serum ferritin, transferrin, erythropoietin or soluble transferrin receptor levels on Day 1 or 7.Summary/Conclusion:VIT‐2763 administered at single oral doses up to 240 mg, or multiple oral doses up to 120 mg BID was safe and well tolerated and achieved rapid and prominent decreases in circulating iron levels in healthy subjects. This iron‐lowering pharmacodynamic effect is consistent with observations in preclinical models. Results of this study support the initiation of a proof‐of concept study of VIT‐2763 in patients with β‐thalassemia and documented iron overload.image